It is known that the benzazepine compounds of the formula (1) have vasopressin antagonistic activity and are useful as a vasodilator, hypotensive agent, diuretic agent, platelet aggregation inhibitor, etc. (cf. WO 91/05549, U.S. Pat. Nos. 5,258,510, 5,753,677, JP-A-6-80641) and further that those compounds are also useful as an oxytocin antagonist (WO 94/01113), a cataract treating agent (WO 94/18975, U.S. Pat. No. 5,827,862), a cerebral edema treating agent (JP-A-8-157368), a Meniere's disease treating agent (JP-A-10-120592), or an antiulcer agent (JP-A-7-188021).
Despite significant advances in the prevention and treatment of cardiovascular disease in the United States over the past two decades, as reflected by a 50% reduction in age-specific mortality from coronary artery disease (CAD) (American Heart Association, Heart and Stroke facts: 1996 statistical supplement, Page 15), the prevalence of heart failure has been steadily increasing (Massie B M, Shah N B, The heart failure epidemic, Curr. Opin. Cardiol. 1996, 11:221-226). This is most likely a result of the aging of the US population and the greater longevity of CAD patients. Approximately five million individuals currently have chronic congestive heart failure, and it has been estimated that 400,000 new cases of heart failure are diagnosed each year (Massie B M, Shah N B, The heart failure epidemic, Curr. Opin. Cardiol. 1996, 11:221-226). And approximately 20% of the patients need to be hospitalized each year for worsening of the disease state (“Cardium”, published by Decision Resources (1998)). It has been shown that approximately 50% of patients with heart failure die within 5 years of their diagnosis (Konstam M, Dracut K, Baker D, et al., Heart failure: evaluation and care of patients with left ventricular dysfunction, AHCRP Publication No. 94-0612, Rockville (MD): US Department of Health and Human Service; June 1994).
In the United States, the cost of treating heart failure has been estimated to be in excess of $12 billion annually and as high as $30 billion, excluding costs related to lost wages and productivity (Levitz K R, Lazenby H C, Cown C A, et al., National health expenditures, 1990, Health Care Fin Rev 1991, 13:29-54; O'Connell J B, Bristow M R, Economic impact of heart failure in the United States: time for a different approach, J Heart Lung Transplant 1994, 13:107-12). The cost of hospitalization alone exceeds $7 billion (O'Connell J B, Bristow M R, Economic impact of heart failure in the United States: time for a different approach, J Heart Lung Transplant 1994, 13:107-12).
Heart failure can be defined as a complex clinical syndrome characterized by abnormalities of left ventricular function and neurohormonal regulation, which in turn can result in effort intolerance, fluid retention, and reduced longevity.
The heart failure is classified to “acute heart failure” and “chronic heart failure” or “chronic heart failure in acute exacerbation” based on the clinical symptoms and the disease course.
The therapeutic measures for heart failure are entirely different depending on the conditions, i.e., whether it is in the chronic phase or in the acute phase. For the treatment of the chronic heart failure, it is treated so as to release the remaining heart failure symptom and to maintain in the stable state so that the symptom does not fall into chronic heart failure in acute exacerbation. On the other hand, when the patient falls into chronic heart failure in acute exacerbation, the symptom may possibly change rapidly for the worse and there is threat to life, and hence, from this viewpoint, it is necessary to take a life-saving measure by temporarily controlling the breath and blood pressure and administering a cardiotonic drug so as to moderate and stabilize the clinical symptoms, in hemodynamic viewpoint, by increasing cardiac output, decreasing intravascular circulation volume, and increasing renal blood flow.
Since most heart failures can not be treated by causal therapy, the symptoms change gradually for the worse with the lapse of time. Even though the cardiac function is temporarily recovered by a temporary symptomatic therapy, the function changes for the worse later and it is impossible to effect a permanent cure. The worsening rate varies depending on various conditions such as the kinds of underline diseases, severity of the disease, effectiveness of therapy, and living environment. Besides, the patients sometimes unexpectedly suddenly die, even while they have been in the favorable course of recovering. The patients of heart failure have bad prognosis as to the life. According to the statistics by Framingham Study in the U.S.A. including the data of all patients suffering from heart diseases, the 50% survival rate is shown in about 4 years since onset of the disease (Kannel, W B, et al., 1982, Mckee, P A, et al., 1982). Besides, in New York Heart Association Class, the patients suffering from the disease in the severity I of the disease, they show good prognosis, but the patients have the severity IV of the disease show the 50% survival rate in less than 1 year, that those having the severity II or III of the disease show the 50% survival rate in less than 4 years. Thus, the patients, who are diagnosed to be severe heart failure, have bad prognosis. (cf. Integrated Handbook of Internal Medicine, Volume 30, 1990, Nakayma Shoten)